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11.06.2019 | Article

miR-17-92 and miR-106b-25 clusters regulate beta cell mitotic checkpoint and insulin secretion in mice

verfasst von: Amitai D. Mandelbaum, Sharon Kredo-Russo, Danielle Aronowitz, Nadav Myers, Eran Yanowski, Agnes Klochendler, Avital Swisa, Yuval Dor, Eran Hornstein

Erschienen in: Diabetologia | Ausgabe 9/2019

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Abstract

Aims/hypothesis

Adult beta cells in the pancreas are the sole source of insulin in the body. Beta cell loss or increased demand for insulin impose metabolic challenges because adult beta cells are generally quiescent and infrequently re-enter the cell division cycle. The aim of this study is to test the hypothesis that a family of proto-oncogene microRNAs that includes miR-17-92 and miR-106b-25 clusters regulates beta cell proliferation or function in the adult endocrine pancreas.

Methods

To elucidate the role of miR-17-92 and miR-106b-25 clusters in beta cells, we used a conditional miR-17-92/miR-106b-25 knockout mouse model. We employed metabolic assays in vivo and ex vivo, together with advanced microscopy of pancreatic sections, bioinformatics, mass spectrometry and next generation sequencing, to examine potential targets of miR-17-92/miR-106b-25, by which they might regulate beta cell proliferation and function.

Results

We demonstrate that miR-17-92/miR-106b-25 regulate the adult beta cell mitotic checkpoint and that miR-17-92/miR-106b-25 deficiency results in reduction in beta cell mass in vivo. Furthermore, we reveal a critical role for miR-17-92/miR-106b-25 in glucose homeostasis and in controlling insulin secretion. We identify protein kinase A as a new relevant molecular pathway downstream of miR-17-92/miR-106b-25 in control of adult beta cell division and glucose homeostasis.

Conclusions/interpretation

The study contributes to the understanding of proto-oncogene miRNAs in the normal, untransformed endocrine pancreas and illustrates new genetic means for regulation of beta cell mitosis and function by non-coding RNAs.

Data availability

Sequencing data that support the findings of this study have been deposited in GEO with the accession code GSE126516.

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Titel: miR-17-92 and miR-106b-25 clusters regulate beta cell mitotic checkpoint and insulin secretion in mice
verfasst von: Amitai D. Mandelbaum
Sharon Kredo-Russo
Danielle Aronowitz
Nadav Myers
Eran Yanowski
Agnes Klochendler
Avital Swisa
Yuval Dor
Eran Hornstein
Publikationsdatum: 11.06.2019
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 9/2019
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-019-4916-z

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miR-17-92 and miR-106b-25 clusters regulate beta cell mitotic checkpoint and insulin secretion in mice

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